AIDS Dementia Complex (ADC) affects up to 50% of adult AIDS patients. Pathological hallmarks of ADC include astrogliosis, demyelination, multinucleated giant cell (MNGC) formation, neuronal degeneration, and enhanced blood-brain barrier (BBB) permeability. Astrocytes and microglia are important cellular participants in mediating neurologic dysfunction associated with ADC, and HIV components such as the envelope glycoprotein gpl20 can alter the functional activities of these cells. Recent work from our laboratories demonstrated that HIV gp 120 can induce expression of intercellular adhesion molecule-1 (ICAM-1) in both rat and human astrocytes and microglia. The signal transduction events involved in gp120-mediated ICAM-l expression involve activation of both protein kinase C (PKC) and tyrosine kinase (TK). Moreover, we have identified two substrates for gpl20-mediated tyrosine phosphorylation in glial cells; the Janus Kinase JAK2, and signal transducer and activator of transcription (STAT-1alpha). This is the first demonstration that gpl20 intracellular signaling involves activation of the JAK/STAT pathway. ICAM-1 is involved in cell extravasation into inflamed tissue, and is critical for the generation of immune responses. We hypothesize that gp12O induction of ICAM-1 expression by glial cells is detrimental because of the involvement of ICAM-1 with extravasation of HIV-1 infected monocytes across the BBB; MNGC formation between infected and uninfected macrophages/microglia; and promoting cellular interactions between HIV-infected macrophages/microglia and astrocytes, contributing to neurotoxin production. In this application, we will further our analysis of how gpl20-induced ICAM-1 expression by glial cells is regulated, and assess the functional significance of ICAM-1 expression by glial cells. In Aim #1, we will delineate the molecular basis by which gpl20 induces ICAM-1 expression in astrocytes and microglia. We will then test the hypothesis that gpl20- mediated ICAM-1 expression in glial cells contributes to many of the detrimental events associated with ADC (Aim #2). The involvement of ICAM- 1 in enhancing HIV- 1 infected monocyte extravasation through the BBB and MNGC formation will be tested. In Aim #3, we will expand on our novel results demonstrating that gpl20 signaling involves activation of the JAK/STAT pathway and PKC by further elucidating how these intracellular signaling molecules contribute to ICAM-1 expression. Lastly, we will determine whether cytokines such as IL-6, IL-l0, and TGF-beta can downregulate gpl20-induced ICAM-1 expression and function by glial cells (Aim #4). The rationale for this aim is our previous data indicating that cytokine-induced ICAM-1 expression is inhibited by IL- 10, and TGF-beta. These studies will help delineate potential avenues of therapeutic intervention during HIV-1 infection of the brain.